Preliminary findings in our laboratory indicate that intercalating agents, and also polylysine, stimulate eN-methylation of certain internal histone lysine residues in rat liver nuclei incubated in the presence of S-adenosyl-methionine, whereas several carcinogenic agents inhibit this process to different degrees. The same agents had no effect or inhibited the activity of the isolated nuclear lysine N-methyltransferase. This pronounced effect by a relatively small change in DNA structure suggests that the polar, methylatable part of arginine-rich histone molecules, DNA and methyltransferase are situated in close proximity in the chromatin complex. Intercalating agents can therefore be used to probe chromatin structure by this new approach. In addition, polylysine was also found to stimulate this process under the same conditions, with a maximum appearing at lysine/phosphate ratio: 0.5. We propose to extend these studies as follows: 1. A study on the effect of pH and ionic strength and phase of the cell cycle on intercalation and stimulation of histone N-methylation by intercalating agents in isolated nuclei and chromatin. (Activity, histone fractions involved, moiety of me-lysine). 2. Compare the effect of carcinogens and intercalating agents on histone methylation in condensed and diffuse chromatin, and in isolated llS chromatin particles. 3. A study on the effect of the composition on inhibition or stimulation. 4. A study on the effect of histone content of reconstituted DNA/histone/enzyme complexes on histone N-methylation. 5. The effect of intercalating agents and carcinogens on the other histone modifications: acetylation and phosphorylation. BIBLIOGRAPHIC REFERENCES: Baxter, C.S., and Byvoet, P. Intercalating Agents as Probes of the Spatial Relationship Between Chromatin Components. Biochem. Biophys. Res. Commun. 62:286, 1975. Byvoet, P. and Baxter, C.S. Histone Methylation, a Functional Enigma. In Chromosomal Proteins and Their Role in the Regulation of Gene Expression. Academic Press. November 1975.